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RapaCaspase-9-based suicide gene applied to the safety of IL-1RAP CAR-T cells

Lucie Bouquet1, Elodie Bôle-Richard1, Walid Warda2

  • 1Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25 000, Besançon, France.

Gene Therapy
|May 12, 2023
PubMed

Insights

Researchers developed a novel inducible suicide gene system, RapaCasp9-G, for adoptive cell transfer (ACT) therapy. This system enhances safety by allowing controlled T cell elimination with rapamycin, mitigating adverse events in cancer treatment.

Area of Science:

  • Immunotherapy
  • Molecular Biology
  • Oncology

Background:

  • Adoptive cell transfer (ACT) shows clinical promise but faces safety concerns due to adverse events.
  • Suicide gene systems offer a strategy to manage these adverse events in ACT therapies.
  • A chimeric antigen receptor (CAR) targeting IL-1RAP is under development for diseases like acute myeloid leukemia (AML).

Purpose of the Study:

  • To develop and evaluate a clinically applicable inducible suicide gene system for enhancing the safety of CAR-based ACT.
  • To assess the efficacy of two RapaCasp9 constructs (RapaCasp9-G and RapaCasp9-A) in controlling gene-modified T cells (GMTCs).
  • To confirm the safety and functionality of the RapaCasp9 system in conjunction with rapamycin administration.

Main Methods:

  • Two inducible suicide gene constructs, RapaCasp9-G and RapaCasp9-A, were designed, incorporating a single-nucleotide polymorphism (rs1052576).
  • Gene-modified T cells (GMTCs) were generated from healthy donors (HDs) and acute myeloid leukemia (AML) patients.
  • In vitro experiments were conducted to assess the functionality and efficiency of the RapaCasp9 constructs under various culture conditions.

Main Results:

  • The RapaCasp9-G construct exhibited superior efficiency compared to RapaCasp9-A.
  • In vitro studies confirmed the functionality of RapaCasp9-G in controlling GMTCs across different clinically relevant conditions.
  • Rapamycin, the activating agent, was demonstrated to be safe for use within the therapeutic context.

Conclusions:

  • The RapaCasp9-G suicide gene system is a promising tool for improving the safety profile of CAR-based ACT therapies.
  • This inducible system allows for controlled elimination of GMTCs, thereby mitigating potential adverse events.
  • The developed system and its activating agent, rapamycin, are suitable for clinical application in ACT, particularly for conditions like AML.

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Caspases

Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside cells.